Identification of a de novo splicing variant in the Coffin-Siris gene, SMARCE1, in a patient with Angelman-like syndrome

Abstract

Background: Patients affected by Angelman syndrome (AS) present severe intellectual disability, lack of speech, ataxia, seizures, abnormal electroencephalography (EEG), and a characteristic behavioral phenotype. Around 10% of patients with a clinical diagnosis of AS (AS-like) do not have an identifiable molecular defect. Some of these patients harbor alternative genetic defects that present overlapping features with AS.

Methods: Trio whole-exome sequence was performed on patient and parent's DNA extracted from peripheral blood. Exome data were filtered according to a de novo autosomal dominant inheritance. cDNA analysis was carried out to assess the effect of the splice site variant.

Results: We identified a novel heterozygous SMARCE1 splicing variant that leads to an exon skipping in a patient with an Angelman-like phenotype. Missense variants in the SMARCE1 gene are known to cause Coffin-Siris syndrome (CSS), which is a rare congenital syndrome. Clinical reevaluation of the patient confirmed the presence of characteristic clinical features of CSS, many of them overlapping with AS.

Conclusions: Taking into account the novel finding reported in this study, we consider that CSS should be added to the expanding list of differential diagnoses for AS.

Keywords: SMARCE1; Angelman syndrome (AS); Coffin-Siris syndrome (CSS); exome sequencing.

Figure 1

Molecular characterization of the SMARCE1 (NCBI RefSeq NM_003079.4) c.237+1G>T splicing variant. (a) Sanger sequencing chromatographs showing the SMARCE1 c.237+1G>T variant in the patient but not in his unaffected parents. The variant is indicated by black asterisks. (b) cDNA analysis of the SMARCE1 c.237+1G>T variant in peripheral blood. PCR amplification products of exons 3 to 7 were run in a gel electrophoresis. The patient showed two bands compared to the negative control. Sanger sequencing chromatographs indicate skipping of exon 5. The start of the exon is indicated by a dashed line. (c) Schematic structure of the human SMARCE1 gene and protein illustrating the predicted variant effect on splicing and protein. Exons are shown as boxes and introns as lines. Protein functional domains are shown as boxes. The amino acid deletion is delimited by black lines. Proline‐rich domain (Pro‐rich) 5–65 aa, High Mobility Group (HMG) 66–134 aa, Coiled‐Coil domain 220–319 aa, glutamic acid‐rich domain (Glu‐rich) 320–411 aa

Figure 2

Patient clinical features. (a) Patient at 5 years of age, (b) 9 years of age, (c) 14 years of age, (d) Left hand showing small and hypoplastic 5th fingernail